Chapter 18 Recent Progress on Novel HCV Inhibitors

Abstract

Publisher Summary Hepatitis C virus (HCV) is a blood-borne pathogen belonging to the Flaviviridae family of viruses, which also includes the West Nile, Yellow Fever, and Dengue viruses. Most small molecule inhibitor approaches to HCV have been focused on inhibition of essential viral targets, particularly the NS3-4A protease and the NS5B RNA-dependent RNA polymerase although other targets are being pursued. A variety of nucleoside competitive inhibitors of HCV NS5B, the RdRp encoded at the 3´-terminal portion of the HCV genome and required for viral replication, have also been thoroughly studied and advanced to clinical trials. By analogy to AIDS, where HIV protease plays a crucial role in processing mature virions, HCV uses the NS3-4A (aka NS3) protease in a similar manner making it a very attractive inhibition target. The key difference between the two proteases is that the HIV protease active site forms a well-defined active site while the NS3 protease has a shallow cleft with fewer opportunities to bind to small molecules. As a result, NS3 inhibitors have been generally more complex, more peptide-like and larger than those for HIV.